DESCRIPTION (Applicant's abstract): Corticotropin releasing factor (CRF) controls the anterior pituitary secretion of adrenocorticotropin and other propiomelanocortin products. CRF also coordinates the endocrine, behavioral and autonomic responses to stress. The long-term objectives of this proposal are to establish that selective corticotrophin releasing factor receptor subtype 1 (CRF1) antagonists will have therapeutic implications in irritable bowel syndrome (IBS) characterized by altered bowel movement and visceral hypersensitivity. The specific aims will be: 1) to demonstrate specific tissue localization of CRF1 receptors in the colon; 2) to identify and synthesize centrally acting vs. peripherally acting high affinity CRF1 receptor non-peptide antagonists; and 3) to examine both centrally acting and peripherally acting CRF1 antagonists in models of stress-related colonic motor stimulation and visceral hypersensitivity in rodents for potential utility in IBS. This will be achieved using novel tools including C-terminal CRF1 receptor antibodies, selective CRF1 receptor antagonists and experimental models to assess distal colonic motor function and visceromotor response to colorectal distension. Based on the co-morbidity between anxiety/depression and IBS and stress-related onset or enhanced IBS symptomatology, these pre-clinical studies will provide the key information needed to pursue a novel therapeutic approach for IBS using Neurocrine CRF1 receptor antagonists and to further develop this therapeutic approach in Phase II studies.